Regulation of Appetite and Obesity by PACAP

PACAP 调节食欲和肥胖

• 批准号: 8480601
• 负责人: Patricia Maria Germano
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8480601
• 关键词: Accounting; Address; Adult; Affinity; Afghanistan; Animal Feed; Animal Model; Animals; Appetite Regulation; Biological; Blood; Body Composition; Body Weight; Body fat; Caring; Cell model; Cells; Cellular biology; Cerebrovascular Disorders; Cessation of life; Chronic; Clinical; Clinical Research; Coronary Arteriosclerosis; Data; Department of Defense; Desire for food; Development; Diabetes Mellitus; Diet; Diet Monitoring; Dietary Proteins; Disease; Eating; Eating Behavior; Enterochromaffin Cells; Equipment; Fatty acid glycerol esters; Feeding behaviors; Financial compensation; Functional disorder; Future; Gastric mucosa; Gastrointestinal Hormones; Gastrointestinal tract structure; Gene Expression; Goals; Hormones; Human; Hyperphagia; Hypertension; Hypothalamic structure; In Vitro; Ingestion; Investigation; Leptin; Mass Behavior; Measurement; Measures; Mediating; Medical; Medical center; Military Personnel; Modeling; Molecular Biology; Molecular Profiling; Morbidity - disease rate; Mucous Membrane; Mus; Neuroendocrine Cell; Neuropeptides; Neurosecretory Systems; Obesity; PACAPR-1 protein; Pathway interactions; Patients; Pensions; Peptide Signal Sequences; Peptides; Peripheral; Physiological; Play; Prevalence; Proteins; Regulation; Regulatory Pathway; Rehabilitation therapy; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Satiation; Secretory Cell; Serum; Signal Transduction; Signal Transduction Pathway; Stomach; Stroke; System; Techniques; Veterans; War; World Health Organization; abdominal fat; adipokines; analog; base; cytokine; design; feeding; gastrointestinal; genetic profiling; ghrelin; glucagon-like peptide 1; in vivo; interdisciplinary collaboration; mortality; mouse model; neurophysiology; novel strategies; novel therapeutics; obesity treatment; pandemic disease; pituitary adenylate cyclase activating polypeptide; preclinical study; programs; public health relevance; receptor; response; therapeutic target; translational study

DESCRIPTION (provided by applicant): The World Health Organization (WHO) has classified obesity as a worldwide pandemic, resulting in about 300,000 deaths per year in U.S. adults and $80 billion in expenses (1-11). Obesity is a major cause of morbidity and mortality within our VA medical system accounting for the majority of cases of diabetes mellitus, hypertension, coronary artery disease and cerebrovascular accidents. The current understanding of the regulation of eating behavior and obesity suggests that both central and peripheral receptors and pathways control appetite. High protein diets have been described to reduce appetite, but the mechanisms are unknown. Our research program has been focused on the role of the recently discovered neuropeptide, Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) and its high affinity receptor, PAC1, in the regulation of appetite and in the development of obesity. PACAP is released in the hypothalamus, where it acts with a dual mechanism: it activates the anorexigenic alpha- melanocortin pathway and it stimulates the release of the orexigenic PYY neuropeptide. The peripheral pathway by which PACAP regulates appetite has not been previously explored. Previously, we have shown that PACAP is released from the gastric mucosa cells in response to meal stimulation and that neuroendocrine of the stomach express PAC1 to regulate gastrointestinal physiological function. For this proposal, we have developed a PAC1 deficient mouse model (PAC1-/-) and have demonstrated that these mice develop hyperphagia and obesity and thus serve as a useful model to investigate the regulatory pathways mediating obesity. Based on these preliminary data, our central hypothesis is that PACAP, released in the stomach following protein ingestion, stimulates PAC1 expressed on gastric neuroendocrine cells to inhibit ghrelin release, thereby suppressing appetite. Accordingly, in Aim 1 of the proposal we will study the relationship between dietary protein content, PACAP release and effects on the downstream pathways connecting PAC1 and ghrelin release. To accomplish this we propose to utilize our PAC1 deficient mice and assess the response to protein dietary content, body mass and feeding behavior. The feeding behavior will be analyzed using our recently acquired BIODAQ equipment, EchoMRI to measure mouse fat and lean mass. The serum levels of PACAP, ghrelin and of a panel of obesity associated hormones and cytokines will be measured using Luminex. The second specific aim of the proposal will investigate the in vitro cellular responses to luminal protein using our recently developed cellular isolation techniques. Microarray and RT-PCR studies will be used to analyze genetic profiles of isolated ECL and X/A. A clear understanding of the key pathophysiological mechanisms underlying these PACAP- induced regulatory pathways involved in appetite/satiety regulation, will allow the design of future clinical studies with a focus on therapy. The proposed studies will elucidate the peripheral mechanisms, by which PACAP influences protein-induced satiety which will provide an important therapeutic target for the development of novel therapeutic compounds which would be used to treat obesity in our Veterans and active duty military personnel. PUBLIC HEALTH RELEVANCE: Within the VA Medical Care Centers and Department of Defense, the prevalence of obesity has been increasing over the past decade and is a major cause of morbidity, mortality and making rehabilitation more difficult for our Veterans. The increasing prevalence of obesity not only leads to the development of chronic medical conditions, such as diabetes mellitus, hypertension, coronary artery disease and cerebrovascular disease, but also it is likely to be a reason for compensation and pension benefits for many of our returning Gulf and Afghanistan War Veterans. Accordingly, this proposal is directed at understanding key gastrointestinal mechanisms for regulating feeding behavior using our recently developed animal model of obesity with the overarching purpose of applying these finding to develop novel approaches for clinically regulating appetite, body composition and weight in veteran patients with obesity- related disorders.

描述（由申请人提供）： 世界卫生组织 (WHO) 将肥胖列为世界范围内的流行病，每年导致美国成年人约 30 万人死亡，并造成 800 亿美元的支出 (1-11)。 肥胖是我们 VA 医疗系统中发病和死亡的主要原因，占糖尿病、高血压、冠状动脉疾病和脑血管意外病例的大多数。目前对饮食行为和肥胖调节的理解表明，中枢和外周受体和通路都控制食欲。高蛋白饮食已被描述为降低食欲，但其机制尚不清楚。我们的研究项目重点关注最近发现的神经肽、垂体腺苷酸环化酶激活多肽 (PACAP) 及其高亲和力受体 PAC1 在食欲调节和肥胖发展中的作用。 PACAP 在下丘脑中释放，以双重机制发挥作用：激活抑制食欲的 α-黑皮质素途径，并刺激抑制食欲的 PYY 神经肽的释放。 PACAP 调节食欲的外周途径此前尚未被探索过。 此前，我们已经证明，胃粘膜细胞响应膳食刺激而释放PACAP，并且胃的神经内分泌表达PAC1来调节胃肠道生理功能。对于这项提议，我们开发了 PAC1 缺陷小鼠模型 (PAC1-/-)，并证明这些小鼠会出现食欲过盛和肥胖，因此可作为研究介导肥胖的调节途径的有用模型。基于这些初步数据，我们的中心假设是，摄入蛋白质后胃中释放的 PACAP 会刺激胃神经内分泌细胞上表达的 PAC1，从而抑制胃饥饿素的释放，从而抑制食欲。因此，在该提案的目标 1 中，我们将研究膳食蛋白质含量、PACAP 释放以及对连接 PAC1 和 ghrelin 释放的下游途径的影响之间的关系。为了实现这一目标，我们建议利用 PAC1 缺陷小鼠来评估对蛋白质饮食含量、体重和进食行为的反应。我们将使用我们最近购买的 BIODAQ 设备 EchoMRI 来分析喂养行为，以测量小鼠的脂肪和瘦肉质量。将使用 Luminex 测量 PACAP、生长素释放肽以及一组肥胖相关激素和细胞因子的血清水平。该提案的第二个具体目标是使用我们最近开发的细胞分离技术研究体外细胞对腔蛋白的反应。 微阵列和 RT-PCR 研究将用于分析分离的 ECL 和 X/A 的基因谱。清楚地了解这些 PACAP 诱导的食欲/饱腹感调节途径背后的关键病理生理机制，将有助于设计未来以治疗为重点的临床研究。拟议的研究将阐明 PACAP 影响蛋白质诱导的饱腹感的外围机制，这将为开发用于治疗退伍军人和现役军事人员肥胖的新型治疗化合物提供重要的治疗靶点。 公共卫生相关性： 在退伍军人管理局医疗中心和国防部内，肥胖症的患病率在过去十年中一直在增加，是发病率、死亡率的主要原因，并使我们的退伍军人康复更加困难。肥胖症的日益流行不仅导致糖尿病、高血压、冠状动脉疾病和脑血管疾病等慢性疾病的发展，而且也可能成为我们许多返回海湾地区的补偿和养老金福利的一个原因和阿富汗战争退伍军人。因此，该提案旨在利用我们最近开发的肥胖动物模型来了解调节进食行为的关键胃肠机制，总体目的是应用这些发现来开发临床调节老年肥胖患者食欲、身体成分和体重的新方法。相关疾病。